title: Pro-inflammatory cytokines can act as intracellular modulators of commensal bacterial virulence.
abstract: Interactions between commensal pathogens and hosts are critical for disease development but the underlying mechanisms for switching between the commensal and virulent states are unknown. We show that the human pathogen Neisseria meningitidis, the leading cause of pyogenic meningitis, can modulate gene expression via uptake of host pro-inflammatory cytokines leading to increased virulence. This uptake is mediated by type IV pili (Tfp) and reliant on the PilT ATPase activity. Two Tfp subunits, PilE and PilQ, are identified as the ligands for TNF-α and IL-8 in a glycan-dependent manner, and their deletion results in decreased virulence and increased survival in a mouse model. We propose a novel mechanism by which pathogens use the twitching motility mode of the Tfp machinery for sensing and importing host elicitors, aligning with the inflamed environment and switching to the virulent state.
authors.affiliation: School of Life Sciences, Molecular Bacteriology and Immunology Group, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Jafar
authors.initials: J
authors.lastname: Mahdavi
authors.forename: Pierre-Joseph
authors.initials: PJ
authors.lastname: Royer
authors.forename: Hong S
authors.initials: HS
authors.lastname: Sjölinder
authors.forename: Sheyda
authors.initials: S
authors.lastname: Azimi
authors.forename: Tim
authors.initials: T
authors.lastname: Self
authors.forename: Jeroen
authors.initials: J
authors.lastname: Stoof
authors.forename: Lee M
authors.initials: LM
authors.lastname: Wheldon
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Brännström
authors.forename: Raymond
authors.initials: R
authors.lastname: Wilson
authors.forename: Joanna
authors.initials: J
authors.lastname: Moreton
authors.forename: James W B
authors.initials: JW
authors.lastname: Moir
authors.forename: Carina
authors.initials: C
authors.lastname: Sihlbom
authors.forename: Thomas
authors.initials: T
authors.lastname: Borén
authors.forename: Ann-Beth
authors.initials: AB
authors.lastname: Jonsson
authors.forename: Panos
authors.initials: P
authors.lastname: Soultanas
authors.forename: Dlawer A A
authors.initials: DA
authors.lastname: Ala'Aldeen
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D036781:Fimbriae Proteins / Q000235:genetics / Q000378:metabolism*; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008024:Ligands; D016920:Meningitis, Bacterial / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008822:Mice, Transgenic; D009345:Neisseria meningitidis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D036781:Fimbriae Proteins
keywords: Neisseria meningitidis; cytokines; glycosylation; patho-adaptation; transcriptional regulators; type IV pili